Method for purifying an organic compound

ABSTRACT

A method of purifying 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is provided which comprises dissolving crude 5-MeO-DMT in a solvent at a temperature above room temperature, cooling the obtained solution to a temperature below room temperature to precipitate solid 5-MeO-DMT, separating the solid 5-MeO-DMT from the remaining solution and removing solvent from the crystalline 5-MeO-DMT. In the method, the solvent comprises one or more ethers and less than 5 wt % anti-solvent.

TECHNICAL FIELD

The present invention relates to a method of purifying an organiccompound, specifically 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Theinvention furthermore relates to 5-MeO-DMT in a form meeting specificpurity requirements.

BACKGROUND

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) has the formula shownbelow.

5-MeO-DMT is a naturally occurring serotonergic psychedelic tryptaminewhich acts as a 5-HT1A and 5-HT2A receptor agonist.

5-MeO-DMT is synthesized in human pineal and retina, and it has beenfound in human body fluids including urine, blood, and cerebrospinalfluid.

5-MeO-DMT was first isolated from the bark of Dictyoloma incanescens,but it is also contained in other plants, and it has been identified asthe major active ingredient in the venom of Bufo alvarius toads.

The chemical synthesis of 5-MeO-DMT has been described in 1936 byHoshino and Shimodaira (Bulletin of the Chemical Society of Japan,11(3), 221-224). No medical or other use is contemplated in thispublication.

According to Hoshino and Shimodaira, following a reaction between5-methoxy indolyl 3-ethyl beta bromide and dimethyl amine the product isisolated and purified by distillation under reduced pressure. It is alsoreported that the substance crystallises from ether-petrol ether. Noconditions are disclosed.

The product obtained is described as nice colorless prisms having amelting point of 66-67° C. There is no characterisation regarding theamounts of impurities contained in the product.

A comparison of the reported melting point with later data regarding themelting point of 5-MeO-DMT (69-70° C.) may, however, be taken as anindication that impurities are still present.

Moreover, given the high boiling point of 5-MeO-DMT even under reducedpressure (208 to 210° C. at 4 mm), distillation is not an advantageouspurification method.

Somei et al. (Chem. Pharm. Bull. 49(1) 87-96 (2001)) report syntheses ofserotonin, N-methylserotonin, bufotenine, 5-methoxy-N-methyltryptamine,bufobutanoic acid, N-(indol-3-yl)methyl-5-methoxy-N-methyltryptamine,and lespedamine.

In the context of a synthesis for bufotenine, a mixture of compoundscomprising 5-MeO-DMT is obtained from which the components are purifiedby column chromatography. 5-MeO-DMT is then recrystallised fromEt₂O-hexane. Details regarding the recrystallisation conditions or theamounts of impurities contained in the product are not disclosed. Theliquid mixture used for recrystallisation (Et₂O-hexane) is similar tothe mixture used by Hoshino and Shimodaira (ether-petrol ether).

Based on its physiological activities, there has recently been aninterest in potential medical uses of 5-MeO-DMT, for instance,investigating potential medical uses in human clinical trials.

For such uses in human clinical trials, and for potential use in anapproved medical product, 5-MeO-DMT in high purity is required. Foradministration to humans, purity as high as possible is necessary.According to the invention, it is in particular desirable that the totalamount of impurities in the drug substance is below 0.5% and that theamount of each individual impurity is below 0.1%.

Furthermore, limits as regards the amount of residual solvent are to beobserved.

Against this background, there is a need for providing a simple methodof purifying 5-MeO-DMT, in particular of purifying 5-MeO-DMT so as toobtain the substance in a pharmaceutical grade. There is also a need forproviding a 5-MeO-DMT in a form meeting specific purity requirements.

SUMMARY OF THE INVENTION

The present invention relates to a method of purifying5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). The method comprises

-   -   dissolving crude 5-MeO-DMT in a solvent at a temperature above        room temperature;    -   cooling the obtained solution to a temperature below room        temperature to precipitate solid 5-MeO-DMT;    -   separating the solid 5-MeO-DMT from the remaining solution;    -   removing solvent from the crystalline 5-MeO-DMT;    -   wherein the solvent comprises one or more ethers and less than 5        wt % of aliphatic hydrocarbons as anti-solvents.

The invention further provides a method comprising the steps as above,wherein the solvent comprises less than 5 wt % in total of anyanti-solvents, wherein anti-solvent means a liquid in which thesolubility of 5-MeO-DMT at any temperature occurring during therecrystallisation is less than 20% the solubility in the ether used, or,in case that more than one ether is used, in the combination of etherspresent in the dissolution solvent.

The invention also provides 5-MeO-DMT in a form containing a totalamount of impurities of below 0.5 area %, wherein the amount of eachindividual impurity is below 0.1 area %. The amounts of impurities aredetermined by chromatography as describes in detail below.

Specific embodiments are defined in the dependent claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an example chromatogram for a 5-MeO-DMT sample analysed byHPLC as described below.

FIG. 2 shows an enhanced view of the example chromatogram.

FIG. 3 is a diagram obtained by plotting the peak area, determined byHPLC, vs the concentration of 5-MeO-DMT in the analysed sample.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) can be purified to obtainthe substance in a pharmaceutical grade by recrystallisation if specificconditions are observed.

5-MeO-DMT is available from natural sources as well as via syntheticmethods. It is a white to off white, yellow or orange powder.

The preparation of 5-MeO-DMT by isolation from natural sources or bychemical synthesis as a rule yields a material (crude 5-MeO-DMT) stillcontaining significant amounts of impurities so that the material is notsuitable for pharmaceutical applications.

The crude 5-MeO-DMT will typically contain a total amount of impuritiesof 0.5% or more and may contain individual impurities in amounts of 0.1%or more.

Preferably, the crude 5-MeO-DMT used in the method of the invention doesnot contain more than 5% impurities in total, more preferably not morethan 2% impurities in total.

While colouration of 5-MeO-DMT shows the presence of one or moreimpurities, it does not as such indicate whether or not a certainpreparation meets the requirements for a pharmaceutical use.

The purity of a 5-MeO-DMT sample is analysed by HPLC. Individualimpurities can be identified by their relative retention times (RRT).The detection method is UV detection at 227 nm.

A suitable column is a reversed-phase column, in particular an octadecylcarbon chain-bonded silica (C18) column.

For elution, a mixed solvent is used which is based on a mobile phase A(0.013M ammonium acetate in water) and a mobile phase B (acetonitrile).A specific gradient method is detailed in Example 1 below.

Percent values referring to purity are area %, based on the peak area inan HPLC chromatogram obtained as described above.

The present inventors have recognised that recrystallisation of crude5-MeO-DMT in the form of the free base, despite its relatively lowmelting point, is a suitable approach to obtain 5-MeO-DMT in highpurity, i.e., in a form having a purity such that the total amount ofimpurities is below 0.5% and the amount of each individual impurity isbelow 0.1%.

While 5-MeO-DMT may separate from a solution upon cooling in the form ofan oil, the inventors have found that solvents comprising certain etherscan suitably be used to obtain a solid, in particular crystalline, formof 5-MeO-DMT having improved purity.

The recrystallisation solvent in particular comprises one or more ethershaving a boiling point in the range of 40° C. to 100° C. under apressure of 1 bar.

Suitable ethers are aliphatic and alicyclic ethers. These ethers inparticular do not comprise any functional group besides the ethermoiety.

Examples of suitable ethers (boiling points in brackets) includedi-n-propylether (90° C.), di-iso-propylether (69° C.), methyltert.-butyl ether (MTBE) (55° C.), ethyl tert.-butyl ether (ETBE) (73°C.), tert.-amyl methyl ether (TAME; 2-methoxy-2-methylbutan) (86° C.),dimethoxymethan (42.3° C.), diethoxymethan (88° C.), tetrahydrofuran(66° C.), (+/−)-tetrahydro-2-methylfuran (80° C.),tetrahydro-2,5-dimethylfuran (90-92° C.), tetrahydropyran (88° C.).

Preferably, the ether has a boiling point in the range of 50° C. to 80°C. under a pressure of 1 bar.

Examples of preferred ethers are methyl tert.-butyl ether (MTBE), ethyltert.-butyl ether (ETBE), and diisopropyl ether. The most preferredether is methyl tert.-butyl ether (MTBE).

The recrystallisation solvent contains at least 50%, preferably at least70% and in particular at least 90% of one or more ethers, in particularof one or more ethers having a boiling point in the range of 40° C. to100° C. under a pressure of 1 bar, especially of one or more of theethers specifically identified above. These % values are intended todesignate wt %, based on the total weight of the solvent.

While other solvents may be present besides the one or more ethers, therecrystallisation solvent contains less than 5%, preferably less than2%, more preferably less than 1%, of aliphatic hydrocarbons asanti-solvents and in particular contains no aliphatic hydrocarbons.Preferably, these limitations apply to any hydrocarbon.

The above % values are intended to designate wt %, based on the totalweight of the recrystallisation solvent, including hydrocarbonanti-solvents.

Further, preferably, while other solvents may be present besides the oneor more ethers, the recrystallisation solvent contains less than 5%,preferably less than 2%, more preferably less than 1%, of anyanti-solvents and in particular contains no anti-solvent. These % valuesare intended to designate wt %, based on the total weight of therecrystallisation solvent, including anti-solvents.

If more than one anti-solvent is present, the limitations set out abovefor the anti-solvent relate to the total amount of all anti-solventspresent.

Minor amounts of certain anti-solvents may be present in commerciallyavailable solvents, such as commercially available ethers.

Preferably no anti-solvent is added in the method of the invention.

The term anti-solvent as used herein refers to a liquid in which thesolubility of 5-MeO-DMT at any temperature occurring during therecrystallisation is less than 20% the solubility in the ether used, or,in case that more than one ether is used, in the combination of etherspresent in the dissolution solvent. The solubility is expressed inmg/mL.

Typical anti-solvents include hydrocarbons, such as aliphatichydrocarbons, like petrol ether, heptanes, hexanes; and water.

In a preferred embodiment, the recrystallisation solvent contains atleast 50%, preferably at least 70% and in particular at least 90% ofMTBE. In a specific embodiment, the recrystallisation solvent containsat least 98% MTBE. The % values are intended to designate wt %, based onthe total weight of the solvent.

In a further preferred embodiment, 5-MeO-DMT is purified byrecrystallisation in 98 wt % MTBE without adding a hydrocarbon as ananti-solvent.

The method of the invention involves dissolving crude 5-MeO-DMT in therecrystallisation solvent. The 5-MeO-DMT will be dissolved in therecrystallisation solvent at a dissolution temperature above roomtemperature up to the boiling point of the solvent.

Room temperature means a temperature in the range of 20 to 25° C. Aboveroom temperature means above 25° C., below room temperature below 20° C.

In one embodiment, the 5-MeO-DMT will be dissolved in therecrystallisation solvent at a dissolution temperature in the range of35 to 40° C.

The amount of recrystallisation solvent used is an amount sufficient toachieve complete dissolution at the dissolution temperature.

For instance, an at least 25% saturated solution is achieved. In oneembodiment, the amount is sufficient to achieve a saturated solution atthe dissolution temperature.

Preferably an at least 50% and at most 90% saturated solution isachieved.

After dissolution has occurred, the solution will be cooled to atemperature below room temperature (i.e., below 20° C.) to allowcrystallisation of the 5-MeO-DMT. A suitable temperature range is 0 to20° C. In one embodiment, the temperature is in the range of 7 to 12° C.

The product obtained can be recovered by filtration.

The recrystallisation may be repeated one or more times to improvepurity.

The purification according to the present invention preferably does notinvolve a column chromatography step. Further, the purificationaccording to the present invention does preferably not involve a step ofdistillation of 5-MeO-DMT.

From the product recovered residual solvent can, at least in part, beremoved under reduced pressure. The weight amount of solvent in theproduct is NMT 5000 ppm, preferably NMT 2500 ppm, more preferably NMT500 ppm and in particular NMT 100 ppm.

The method of the invention allows reducing the amount of impurities. Itin particular allows reducing the total amount of impurities in a5-MeO-DMT sample to below 0.5% and reducing the amount of eachindividual impurity in a 5-MeO-DMT sample to below 0.1%. These % valuesare area % determined by HPLC as indicated above. At the same time, lowamounts of residual solvent can be achieved.

Thus, according to one aspect of the invention, 5-MeO-DMT is provided ina form containing a total amount of impurities of below 0.5 area %,wherein the amount of each individual impurity is below 0.1 area %. Theamounts of impurities are determined by HPLC carried out with anoctadecyl carbon chain-bonded silica (C18) column and a mixed solventbased on 0.013M ammonium acetate in water and acetonitrile as eluent,using UV detection at 227 nm.

5-MeO-DMT is provided in a form preferably having a residual solventcontent of not more than 5000 ppm, preferably not more than 2500 ppm,more preferably not more than 500 ppm and in particular not more than100 ppm.

The following examples are intended to further illustrate the invention.

EXAMPLES Example 1—Analytical Method

The purity of 5-MeO-DMT is determined by HPLC.

Method Parameters

-   Instrument: A suitable HPLC system equipped with UV detection,    linked to the laboratory data handling system-   Column: ACE C18 (150×4.6×3 μm)-   Injection Volume: 5 μl-   Flow Rate: 0.75 ml/minute-   Detector: UV at 227 nm-   Run Time: 25 minutes-   Column Temperature: 30° C.-   Diluent: Methanol-   Mobile Phase A: 0.013M Ammonium acetate in water-   Mobile Phase B: Acetonitrile-   Gradient:

Time (minutes) Vol.-% Mobile Phase A Vol.-% Mobile Phase B 0.0 80 2018.0 26 74 20.0 26 74 20.1 80 20 25.0 80 20

The typical retention time of 5-MeO-DMT is 5.5 min.

Sample Preparation (In Duplicate)

Accurately weigh 12-18 mg of sample into 100 ml volumetric flask andmake to volume with methanol. Mix well.

Validation of Analytical Procedures

The HPLC method used was tested for linearity and precision. IR, NMR,GC-Headspace, KF and ICP-MS are common techniques, being appliedaccording to routine procedures. Based on the results, the methods areconsidered as fit for purpose.

Linearity of the HPLC Method

A stock solution of 5-MeO-DMT was prepared in methanol. A nominalconcentration of 0.15 mg/ml was taken.

Actual concentration Peak Area % Nominal (mg/ml) Injection 1 Injection 2mean % RD 150 0.226 132.511 134.435 133.473 1.4 125 0.181 109.305108.094 108.700 −1.1 100 0.151 91.466 92.675 92.070 1.3 80 0.121 73.54372.295 72.919 −1.7 50 0.075 46.871 46.891 46.881 0.0 25 0.038 23.96524.056 24.011 0.4 10 0.015 9.675 9.706 9.690 0.3 5 0.008 4.670 4.6944.682 0.5 1 0.000 0.982 0.989 0.985 0.7 0.1 0.002 0.468 0.472 0.470 0.80.01 0.000 0.097 0.095 0.096 −2.1

All duplicate injections were within ±2%.

Y intercept % at nominal concentration was determined to be 0.8%. Methodis deemed linear, as seen in FIG. 3.

Precision of the HPLC Method

Six sample solutions were prepared at nominal concentration (12-18 mg in100 ml methanol). The purity results were as follows:

Precision Purity (% area) 1 99.21 2 99.02 3 99.18 4 99.21 5 99.17 699.17 Average 99.16 SD 0.07 RSD (%) 0.07

Acceptance criteria for purity values across the six samples would be 1%RSD, the actual reading was 0.07%. Therefore, the analytical method isconsidered to exhibit adequate precision.

Example 2—Solvent Screen

A solubility screen of 5-MeO-DMT was performed on a number of solventsat both room temperature and reflux.

The screen involved adding a solvent to 200 mg of 5-MeO-DMT untilcomplete dissolution was obtained, unless the compound had such a lowsolubility in the solvent that no complete dissolution of the sample wasachieved in 4 ml solvent (solubility less than 0.05 mg/ml).

The results of the solubility screen are shown in the table below.

5-MeO-DMT Solubility Ambient Ambient Reflux Reflux Solvent (g/mL)(vols.) (g/mL) (vols.) Acetone 0.53 1.9 — — Ethanol 0.34 2.9 — — EthylAcetate 0.26 3.9 — — 2-Methyltetrahydrofuran 0.25 4.0 — — (2-MeTHF)Isopropyl acetate 0.21 4.8 — — (IPAc) Toluene 0.2 5.1 — — Isopropanol(IPA) 0.18 5.6 — — Methyl tert-butyl <0.05 >20 0.42 2.4 ether (MTBE)Heptanes <0.05 >20 <0.05 >20 Water <0.05 >20 <0.05 >20

The results from the solubility screen indicated that 5-MeO-DMT was verysoluble in a number of solvents at room temperature. Poor solubility wasobserved in water and heptanes.

5-MeO-DMT was not observed to be soluble in MTBE at room temperature butwas very soluble when the temperature of the solvent was increased.However, MTBE was not considered a suitable recrystallisation solvent asupon cooling of the hot MTBE solution to room temperature nocrystallisation was observed.

Example 3—Initial Attempts at Recrystallisation

Following the results of the solubility study a number of experimentswere performed with the aim of recrystallising 5-MeO-DMT from a mixtureof isopropanol (IPA) and either heptanes or water. The aim was todissolve 5-MeO-DMT in IPA before adding water or heptanes as theanti-solvent to afford precipitation/crystallisation. IPA was used inorder to maximise recovery of the recrystallised 5-MeO-DMT as although5-MeO-DMT was found to be very soluble in IPA at room temperature,5-MeO-DMT was less soluble in IPA than in the other solvents evaluated.

In the first small scale experiment 5-MeO-DMT (200 mg) was dissolved inthe minimum amount of IPA (0.3 mL, 1.5 volumes) required to achievecomplete dissolution at 80° C. After cooling the solution to roomtemperature no crystallisation was observed, however. Therefore,heptanes were added dropwise with the aim of precipitating 5-MeO-DMTfrom solution. Unfortunately, upon the addition of heptanes 5-MeO-DMTwas found to oil rather than precipitate. Oiling also occurred when theexperiment was repeated using water as the anti-solvent in place ofheptanes.

In a second attempt at crystallisation from an IPA and water or heptanesmixture the solvent additions were reversed in an attempt to stopoiling. 9.5 volumes (1.9 mL) of heptanes were charged to 5-MeO-DMT (200mg) before the resulting slurry was warmed to 80° C. IPA (2.1 volumes,0.4 mL) was charged dropwise until complete dissolution was observed.Upon cooling to room temperature, however, the material did notcrystallise. An attempt with water (9.5 volumes, 1.9 mL) and IPA (5.3volumes, 1 mL) also resulted in a lack of crystallisation upon coolingto room temperature.

To investigate whether crystallisation could be achieved using a reducedvolume of the solvent mixtures a 17% IPA in heptanes solution (9.4volumes, 1.9 mL) was added dropwise to 5-MeO-DMT (200 mg), at 80° C.,until all material was completely dissolved. Unfortunately, aftercooling, oiling was observed. Oiling also occurred when a 34% IPA inwater (10.7 volumes) was added to 5-MeO-DMT (200 mg) at 80° C.

The previously described experiments utilising the 17% IPA in heptanesand 34% IPA in water solutions were repeated at 60° C. Unfortunately, inboth cases oiling was observed upon cooling.

A further final small-scale experiment using a solvent in which5-MeO-DMT has greater solubility was carried out. Ethanol (0.5 volumes,0.1 mL) was charged to 5-MeO-DMT (200 mg) at 60° C. before water wasadded dropwise. However, upon addition of water to the batch oiling of5-MeO-DMT was observed.

Table 2 below displays a summary of the small scale recrystallisationtrials described above.

5-MeO-DMT Anti- Experiment charge Solvent solvent Comments IPA addeduntil dissolution 200 mg IPA Heptanes Oiling out during dropwiseachieved at 80° C. addition of heptanes Anti-solvent charged once 200 mgIPA Water Oiling out during dropwise dissolution achieved addition ofwater IPA charged to slurry of 5- 200 mg IPA Heptanes Completedissolution MeO-DMT in anti-solvent at achieved but no 80° C. to achievecomplete crystallisation upon cooling dissolution 200 mg IPA WaterComplete dissolution achieved but no crystallisation upon coolingMixture of IPA in anti-solvent 200 mg IPA Heptanes Complete dissolutioncharged to 5-MeO-DMT at achieved but oiling out upon 80° C. to achievecomplete cooling dissolution 200 mg IPA Water Complete dissolutionachieved but oiling out upon cooling Mixture of IPA in anti-solvent 200mg IPA Heptanes Complete dissolution charged to 5-MeO-DMT at achievedbut oiling out upon 60° C. to achieve complete cooling dissolution 200mg IPA Water Complete dissolution achieved but oiling out upon coolingEthanol added until dissolution 200 mg Ethanol Water Oiling out duringdropwise achieved at 60° C. Anti- addition of water solvent charged oncedissolution achieved

Example 4—Crystallisation After Heating and Oiling

In an attempt to avoid 5-MeO-DMT oiling out during crystallisation alarger scale experiment was performed. With the increased scale, greatercontrol over the anti-solvent charge was expected, allowing more carefuladdition, potential determination of the cloud point and the avoidanceof oiling. 5-MeO-DMT (2.0 g) was warmed to 60° C. before being dissolvedin the minimum amount of IPA (0.8 mL, 0.4 volumes) required to achievecomplete dissolution. After cooling to room temperature nocrystallisation was observed and so the batch was warmed back to 60° C.Water was added dropwise until the solution became cloudy.Unfortunately, no cloud point was determined because of 5-MeO-DMT oilingfrom solution without the solution becoming cloudy.

In order to determine whether it was possible to still crystallise5-MeO-DMT, despite it oiling from solution, the solvent was removed byevaporation to yield an orange oil. After cooling the oil in a fridgeovernight an orange crystalline solid was obtained. This resultindicated that although crystallisation of 5-MeO-DMT was slow it wasstill possible to crystallise 5-MeO-DMT even after heating and oiling.

Example 5—Larger Scale Crystallisation Attempts Using MTBE/Heptanes

Due to the issues encountered when using a solvent mixture of either IPAor ethanol in heptanes or water, a solvent system utilising MTBE wasreinvestigated.

Previously crystallisation from MTBE was not observed following coolingto room temperature. Therefore, in the second attempt atcrystallisation, from MTBE, the solution was further cooled to 0 to 5°C.

MTBE (1 mL, 0.5 volumes) was charged to the crystalline solid at 45 to50° C. until complete dissolution was achieved. This MTBE charge waslower than the 2.4 volumes stated previously and is likely due to thesmall scale that the solvent screen was performed at.

Following dissolution, the batch was cooled to 0 to 5° C. over 40minutes to yield a very thick viscous solution that did affordcrystallisation.

The batch was warmed back to 45 to 50° C. and then cooled to roomtemperature over 1 hour. After stirring at room temperature for 30minutes the batch became a very thick viscous solution and so a further0.4 mL (0.2 volumes) of MTBE was charged before the batch was stirredfor a further 15 minutes. Following the stirring a thin slurry wasobtained.

Heptanes (0.7 mL, 0.35 volumes) were charged dropwise and then the batchwas stirred for an additional 15 minutes resulting in a thicker slurry.The batch was cooled to 0 to 5° C. and heptanes (0.7 mL, 0.35 volumes)were subsequently charged dropwise. Once filtered the isolated solidswere washed with cold heptanes (2×2 mL) before being dried under vacuumovernight to yield a pale orange solid. The isolated solid (1.44 g, 72%recovery) was analysed by HPLC for purity.

Experimental conditions are summarised in Table 3. The results of theanalysis are shown in Table 4.

Example 6—Crystallisation Utilising MTBE/Heptanes

A second experiment utilising MTBE/heptanes was performed. 5-MeO-DMT(2.0 g) was dissolved in MTBE (1.4 mL, 0.7 volumes) at 45 to 50° C.before being cooled to room temperature over 70 minutes. Uponcrystallisation stirring stopped and so the batch was warmed back to 45to 50° C. and additional MTBE (1 mL, 0.5 volumes) was charged. Aftercooling back to room temperature and stirring out the resulting slurrywas diluted with heptanes (1 mL, 0.5 volumes). Upon heptanes addition alarge amount of material was observed to coat the vessel wall and so totry and remove this material a further amount MTBE (1 mL, 0.5 volumes)was charged. After stirring for 90 minutes at room temperature the batchwas filtered then washed sequentially with MTBE:heptanes (2:1, 1 mL, 0.5volumes) and heptanes (1 mL, 0.5 volumes). After drying a pale orangesolid was obtained in 1.13 g (57% recovery). The isolated material wasanalysed for purity by HPLC.

Experimental conditions are summarised in Table 3. The results of theanalysis are shown in Table 4.

Example 7—Crystallisation Utilising MTBE/Heptanes

5-MeO-DMT (2.0 g) was dissolved in MTBE (2 mL, 1.0 volume) at 45 to 50°C. before being cooled to room temperature over 1 hour. After stirringout at room temperature for 1.5 hours the resulting slurry was dilutedwith MTBE (2×1 mL, 1.0 volume) over 20 minutes. Heptanes (1 mL, 0.5volumes) were then charged over 5 minutes before the batch was stirredat room temperature for 2 hours. After cooling to 8 to 12° C. over 10minutes the batch was stirred for 15 minutes at 8 to 12° C. before beingdiluted with more heptanes (1 mL, 0.5 volumes). After an additional 10minutes stir out at 8 to 12° C. the batch was cooled to 0 to 5° C. over10 minutes then stirred out for a further 15 minutes. Heptanes (2 mL,1.0 volume) were then charged over 5 minutes before the batch wasstirred at 0 to 5° C. for 1 hour. The batch was filtered and washed withMTBE:heptanes (1:1, 2 mL, 1.0 volume). After drying a pale orange solidwas obtained in 1.37 g (69% recovery). The isolated solid was analysedfor purity by HPLC.

Experimental conditions are summarised in Table 3. The results of theanalysis are shown in Table 4.

Example 8—Crystallisation from MTBE

In order to try and further increase the purity of the recrystallisedmaterial an experiment was performed using only MTBE as the solvent.5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 volumes) at 35 to 40°C. before being cooled to room temperature over 30 minutes. Afterstirring at room temperature for 50 minutes no crystallisation wasobserved, therefore, the batch temperature was decreased to 7 to 12° C.over 30 minutes. After stirring at 7 to 12° C. for 10 minutescrystallisation occurred. The batch was subsequently filtered followinga 1 hour stir out at 7 to 12° C. After washing with MTBE (1 mL, 0.5volumes), at 7 to 12° C., the batch was pulled dry under vacuum for 3.5hours to yield a pale orange solid in 1.02 g (50% recovery). Theisolated solid was analysed for purity by HPLC.

Experimental conditions are summarised in Table 3. The results of theanalysis are shown in Table 4.

Table 3 below displays a summary of the conditions of the larger scaleattempts at recrystallisation of 5-MeO-DMT.

Example 5 Example 6 Example 7 Example 8 Input (g) 2.00 2.00 2.00 2.0MTBE:heptanes ratio 1:1 4:1 1:1 No heptanes Total solvent 2.8 4.4 8.04.0 volume (mL) Total solvent 1.2 2.2 4.0 2.0 volume (vols.) Isolation0-5 20-25 0-5 7-12 temperature (° C.) Recovery (g) 1.44 1.13 1.37 1.02Recovery (%) 72 57 69 50 Purity (% area) 99.61 99.58 99.45 99.74

Table 4 below displays impurity profiles of materials isolated fromrecrystallisation experiments.

HPLC Purity (area %) Impurity Profile Raw RRT Material Example 5 Example6 Example 7 Example 8 0.87 0.07 — 0.02 0.02 0.06 0.90 0.04 0.08 0.050.06 0.02 0.92 0.03 0.02 0.02 0.02 — 5-MeO-DMT 1.00 99.21  99.61  99.58 99.45 99.74  1.18 0.13 0.03 0.11 0.14 0.04 1.24 0.15 0.06 0.07 0.05 0.021.28 0.02 — — 0.01 <0.01  1.64 — — — 0.01 0.02 1.67 — — — — <0.01  1.72— — — 0.02 — 1.96 0.02 — — 0.01 — 2.08 — — — 0.01 — 2.11 — — — 0.01 —2.34 0.03 0.02 0.03 0.03 — 2.38 0.29 0.19 0.13 0.14 0.08 2.42 — — — 0.01— 2.61 — — — <0.01 — 2.76 0.01 — — 0.01 — 2.82 — — — 0.01 — 2.90 — — —<0.01 —

A summary of the conditions used in the each of the larger scalerecrystallisation experiments is shown in Table 3. The results from theanalysis indicated that in all cases the overall purity of the materialwas increased and the impurity at RRT 1.24 was purged to below 0.10%.The impurity at RRT 2.38 was also reduced in all three experimentshowever but only below the target of NMT 0.10% in the experimentaccording to Example 8. The impurity at RRT 1.18 was only purged usingthe experimental conditions according to Example 5 and according toExample 8. Based upon these results it appears the most suitableconditions for achieving material in which all impurities are below0.10% are from the experiment according to Example 8. Solvent analysisof sample according to Example 8 indicated an MTBE level of 17 ppmagainst an expected limit of NMT 5000 ppm.

1. Method of purifying 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)comprising dissolving crude 5-MeO-DMT in a solvent at a temperatureabove room temperature cooling the obtained solution to a temperaturebelow room temperature to precipitate solid 5-MeO-DMT separating thesolid 5-MeO-DMT from the remaining solution removing solvent from thecrystalline 5-MeO-DMT wherein the solvent comprises one or more ethersand less than 5 wt % of aliphatic hydrocarbons as anti-solvents. 2.Method according to claim 1, wherein the one or more ethers have boilingpoints in the range of 40° C. to 100° C. under a pressure of 1 bar. 3.Method according claim 1, wherein the one or more ethers are selectedfrom methyl tert.-butyl ether (MTBE), ethyl tert.-butyl ether (ETBE),and diisopropyl ether.
 4. Method according to claim 1, wherein therecrystallisation solvent contains at least 50 wt %, preferably at least70 wt % and in particular at least 90 wt % of one or more ethers. 5.Method according to claim 1, wherein the recrystallisation solventcontains less than 2 wt % aliphatic hydrocarbons.
 6. Method according toclaim 5, wherein the recrystallisation solvent contains less than 1 wt %aliphatic hydrocarbons.
 7. Method according to claim 1, wherein therecrystallisation solvent contains at least 98 wt % MTBE.
 8. Methodaccording to claim 1, wherein the solvent comprises less than 5 wt % intotal of any anti-solvents, wherein anti-solvent means a liquid in whichthe solubility of 5-MeO-DMT at any temperature occurring during therecrystallisation is less than 20% the solubility in the ether used, or,in case that more than one ether is used, in the combination of etherspresent in the dissolution solvent.
 9. Method according to claim 8,wherein the recrystallisation solvent contains less than 2 wt % ofanti-solvents.
 10. Method according to claim 9, wherein therecrystallisation solvent contains less than 1 wt % of anti-solvents.11. Method according to claim 1, wherein the solution is cooled to atemperature in the range of 0 to 20° C.
 12. Method according to claim11, wherein the temperature is in the range of 7 to 12° C.
 13. Methodaccording to claim 1 additionally comprising a step of reducing theamount of remaining recrystallisation solvent.
 14. Method according toclaim 1, wherein the total amount of impurities is reduced to below 0.5area % as determined by HPLC using UV detection at 227 nm and/or whereinthe amount of each individual impurity is reduced to below 0.1 area % asdetermined by HPLC using UV detection at 227 nm.
 15. Method according toclaim 14, wherein the HPLC is carried out with an octadecyl carbonchain-bonded silica (C18) column and a mixed solvent based on 0.013Mammonium acetate in water and acetonitrile as eluent.
 16. Methodaccording to claim 13, wherein the amount of residual solvent in theproduct is not more than 5000 ppm.
 17. 5-Methoxy-N,N-dimethyltryptamine(5-MeO-DMT), wherein the total amount of impurities is below 0.5 area %and wherein the amount of each individual impurity is below 0.1 area %,wherein the amounts of impurities are determined by HPLC carried outwith an octadecyl carbon chain-bonded silica (C18) column and a mixedsolvent based on 0.013M ammonium acetate in water and acetonitrile aseluent, using UV detection at 227 nm.
 18. 5-MeO-DMT according to claim17, wherein in addition the amount of residual solvent is not more than5000 ppm.